An adaptive mutation in enterococcus faecium LiaR associated with antimicrobial peptide resistance mimics phosphorylation and stabilizes LiaR in an activated state

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dc.contributor.authorDavlieva, Milya G.
dc.contributor.authorTovar-Yanez, Angel
dc.contributor.authorDeBruler, Kimberly
dc.contributor.authorLeonard, Paul G.
dc.contributor.authorZianni, Michael R.
dc.contributor.authorArias, César A.
dc.contributor.authorShamoo, Yousif
dc.date.accessioned2020-07-16T15:27:39Z
dc.date.available2020-07-16T15:27:39Z
dc.description.abstractenglishThe cyclic antimicrobial lipopeptide daptomycin (DAP) triggers the LiaFSR membrane stress response pathway in enterococci and many other Gram-positive organisms. LiaR is the response regulator that, upon phosphorylation, binds in a sequence-specific manner to DNA to regulate transcription in response to membrane stress. In clinical settings, non-susceptibility to DAP by Enterococcus faecium is correlated frequently with a mutation in LiaR of Trp73 to Cys (LiaRW73C). We have determined the structure of the activated E. faecium LiaR protein at 3.2 Å resolution and, in combination with solution studies, show that the activation of LiaR induces the formation of a LiaR dimer that increases LiaR affinity at least 40-fold for the extended regulatory regions upstream of the liaFSR and liaXYZ operons. In vitro, LiaRW73C induces phosphorylation-independent dimerization of LiaR and provides a biochemical basis for non-susceptibility to DAP by the upregulation of the LiaFSR regulon. A comparison of the E. faecalis LiaR, E. faecium LiaR, and the LiaR homolog from Staphylococcus aureus (VraR) and the mutations associated with DAP resistance suggests that physicochemical properties such as oligomerization state and DNA specificity, although tuned to the biology of each organism, share some features that could be targeted for new antimicrobials.eng
dc.format.mimetypeapplication/pdf
dc.identifier.doihttps://doi.org/10.1016/j.jmb.2016.09.016
dc.identifier.instnameinstname:Universidad El Bosquespa
dc.identifier.issn1089-8638
dc.identifier.reponamereponame:Repositorio Institucional Universidad El Bosquespa
dc.identifier.repourlhttps://repositorio.unbosque.edu.co
dc.identifier.urihttps://hdl.handle.net/20.500.12495/3526
dc.language.isoeng
dc.publisherElsevierspa
dc.publisher.journalJournal of molecular biologyspa
dc.relation.ispartofseriesJournal of molecular biology, 1089-8638, Vol. 428, Nro. 22, 2016, p. 4503-4519spa
dc.relation.urihttps://www.sciencedirect.com/science/article/abs/pii/S0022283616303953?via%3Dihub
dc.rights.accessrightshttps://purl.org/coar/access_right/c_abf2
dc.rights.accessrightsinfo:eu-repo/semantics/openAccess
dc.rights.accessrightsAcceso abierto
dc.rights.creativecommons2016-11-06
dc.rights.localAcceso abiertospa
dc.subject.decsDaptomicinaspa
dc.subject.decsDiagnóstico por imagenspa
dc.subject.decsEnterococos resistentes a la vancomicinaspa
dc.subject.keywordsLiaRspa
dc.subject.keywordsE. faeciumspa
dc.subject.keywordsResponse regulatorspa
dc.titleAn adaptive mutation in enterococcus faecium LiaR associated with antimicrobial peptide resistance mimics phosphorylation and stabilizes LiaR in an activated statespa
dc.title.translatedAn adaptive mutation in enterococcus faecium LiaR associated with antimicrobial peptide resistance mimics phosphorylation and stabilizes LiaR in an activated statespa
dc.type.coarhttps://purl.org/coar/resource_type/c_6501
dc.type.driverinfo:eu-repo/semantics/article
dc.type.hasversioninfo:eu-repo/semantics/publishedVersion
dc.type.localArtículo de revista

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